Characterization of impaired CD8+ T cell responses to Chlamydia trachomatis.

摘要

Chlamydia trachomatis infection is the most common bacterial sexually transmitted disease in the United States. Irregular screening to identify infected individuals and a lack of sterilizing immunity to C. trachomatis has led to a dramatic increase in the number of reported C. trachomatis infections over the last twenty years. Repeated infections with C. trachomatis lead to serious sequelae such as pelvic inflammatory disease and ectopic pregnancy, which can result in infertility.;It is unclear why the adaptive immune system, specifically the CD8+ T cell response, is unable to protect against subsequent C. trachomatis infections. In this dissertation I first describe the endogenous CD8+ T cell response in the genital mucosa during C. trachomatis infection. I found that primary C. trachomatis infection elicits a robust CD8+ T cell response. However, rechallenge with C. trachomatis produces a secondary CD8+ T cell response that is numerically weaker compared to the primary response. I found that depletion of CD8+ T cells prior to primary or secondary infection has no impact on the host's ability to clear C. trachomatis. All together these data indicate that CD8+ T cells do not contribute to protecting the host against C. trachomatis infection of the genital tract.;In the third chapter I examined the expression of different immuno-inhibitory molecules in the genital tract of C. trachomatis. I focused on further characterizing the expression of the immuno-inhibitory ligand PD-L1. I found that upon infection PD-L1 is highly expressed on epithelial cells of the genital tract and dendritic cells within the draining lymph nodes. Furthermore I show that the receptors for PD-L1, PD-1 and B7-1, are highly expressed on CD8+ T cells after infection has resolved. In the final part of this dissertation I demonstrate that the PD-1/PD-L1 pathway contributes to the defective CD8+ T cell response during C. trachomatis infection. Deletion or inhibition of PD-L1 or PD-1 restores the CD8+ T cell response and enhances C. trachomatis clearance.